Recently, nitric oxide (NO) has received a tremendous amount of attention in the medical community as a selective pulmonary vasodilator for use, for example, (i) in the treatment of pulmonary artery hypertension which is characteristic of severe adult respiratory distress syndrome and (ii) in certain types of surgery. See e.g., McArthur, C., "Putting NO to the Test," The Journal for Respiratory Care Practitioners, 29 (August/September 1994); Bigatello, L. M. et al., "Prolonged Inhalation of Low Concentrations of Nitric Oxide in Patients with Severe Adult Respiratory Distress Syndrome," Anesthesiology, 80:4, 761 (1994); and Feldman, P. L., "The Surprising Life of Nitric Oxide," Chemical & Engineering News, 26 (December 1993). Nitric oxide was first identified as an endogenous vasodilator in 1987. Inhaled nitric oxide has been shown to decrease pulmonary artery pressure in patients with pulmonary hypertension without systemic vasodilation. McArthur, supra.
However, nitric oxide can be toxic. Indeed, the Occupational Safety and Health Administration ("OSHA") has set the time-weighted average of inhaled NO at 25 ppm. Moreover, nitric oxide is an unstable molecule and combines readily with oxygen (O.sub.2) to form nitrogen dioxide (NO.sub.2), which has been shown to cause pulmonary toxicity at very low levels. McArthur, supra. Indeed, OSHA has set the upper limit of inhaled nitrogen dioxide at 5 ppm.
The nitrogen dioxide byproduct is thus potentially more toxic than the nitric oxide and can cause epithelial injury as well as airway hyperreactivity. The conversion of nitric oxide to nitrogen dioxide is dependent upon a number of factors including the nitric oxide dose, the inspired oxygen fraction (FiO.sub.2), dwell time and temperature. Because of the toxicity of both nitric oxide and nitrogen dioxide, it is desirable to maintain the nitric oxide dose at the minimum level suitable to provide a desired therapeutic effect. In that regard, concentrations of nitric oxide as low as 2 ppm have been shown to be effective in improving arterial oxygenation and decreasing mean pulmonary artery pressure. Bigatello, et al., supra.
In light of their potential toxicity, it is recommended in treatment of patients with nitric oxide that nitric oxide and nitrogen dioxide concentrations be continuously monitored inline near the patient. McArthur, supra at 40. Moreover, the method/apparatus used to monitor such concentrations should be capable of resolving very low concentrations of such gases.
Chemiluminescent monitoring has been suggested for evaluating bedside/circuit levels of nitric oxide and nitrogen dioxide during delivery of therapeutic nitric oxide. McArthur, supra at 40-41. Although electrochemical gas sensors are less expensive, easy to use, and easily equipped with alarm systems, they are perceived to have a number of drawbacks in medical use. Most importantly, the sensitivity of electrochemical gas sensors has been questioned. Current electrochemical gas sensors are capable of resolving concentrations in parts per million, whereas chemiluminescent monitoring allows measurement of concentrations in parts per billion. Nevertheless, given the ease of use and inexpensive nature of electrochemical gas sensors it would be very desirable to develop such a sensor suitable for the monitoring of nitric oxide concentrations during therapeutic use.
In an electrochemical gas sensor, the gas to be measured (sometimes referred to as the analyte gas) typically diffuses from the test environment into the sensor housing through a gas porous or gas permeable membrane to a working electrode (sometimes called a sensing electrode) where a chemical reaction occurs. A complementary chemical reaction occurs at a second electrode known as a counter electrode (or an auxiliary electrode). The electrochemical sensor produces an analytical signal via the generation of a current arising directly from the oxidation or reduction of the analyte gas at the working electrode.
To be useful as an electrochemical sensor, a working and counter electrode combination must be capable of producing an electrical signal that is (1) related to the concentration of the analyte and (2) sufficiently strong to provide a signal-to-noise ratio suitable to distinguish between concentration levels of the analyte over the entire range of interest. In other words, the current flow between the working electrode and the counter electrode must be measurably proportional to the concentration of the analyte gas over the concentration range of interest.
In addition to a working electrode and a counter electrode, an electrochemical sensor often includes a third electrode, commonly referred to as a reference electrode. A reference electrode is used to maintain the working electrode at a known voltage or potential. The reference electrode should be physically and chemically stable in the electrolyte and carry the lowest possible current to maintain a constant potential.
Electrical connection between the working electrode and the counter electrode is maintained through an electrolyte. The primary functions of the electrolyte are: (1) to efficiently carry the ionic current; (2) to solubilize the analyte gas; (3) to support both the counter and the working electrode reactions; and (4) to form a stable reference potential with the reference electrode. The primary criteria for an electrolyte include the following: (1) electrochemical inertness; (2) ionic conductivity; (3) chemical inertness; (4) temperature stability; (5) low cost; (6) low toxicity; (7) low flammability; and (8) appropriate viscosity.
Electrochemical gas sensors of the type discussed above are generally disclosed and described in U.S. Pat. Nos. 4,132,616, 4,324,632, 4,474,648; and in European Patent Application No. 0 496 527 A1. A comprehensive discussion of electrochemical gas sensors is also provided in a paper by Cao, Z. and Stetter, J. R., entitled "Amperometric Gas Sensors," the disclosure of which is incorporated herein by reference.
In general, the electrodes of an electrochemical cell provide a surface at which an oxidation or a reduction reaction occurs (that is, an electrochemically active surface) to provide a mechanism whereby the ionic conduction of the electrolyte solution is coupled with the electron conduction of the electrode to provide a complete circuit for a current. It is generally believed that the half cell reactions of the working electrode and the counter electrode, respectively, for nitric oxide electrochemical gas sensors (using H.sub.2 SO.sub.4 as the electrolyte) are as follows: EQU NO+2H.sub.2 O.revreaction.HNO.sub.3 +3H.sup.+ +3e.sup.- EQU O.sub.2 +4H.sup.+ +4e.sup.- .revreaction.2H.sub.2 O
The above reactions result in the following net cell reaction: EQU 4NO+2H.sub.2 O+3O.sub.2 .revreaction.4HNO.sub.3
Although nitric oxide electrochemical gas sensors as described above have been used in industrial settings, current sensors are generally unsuitable for use in medical environments for a number of reasons. As discussed above, such sensors are generally incapable of accurately resolving concentration of nitric oxide foreseen to be used in medical therapy. Moreover, current nitric oxide electrochemical gas sensors such as the Nitric Oxide CiTicels.RTM. available from City Technology of Portsmouth, England are found to be sensitive to (or subject to interference from) other gases commonly used in the medical arts. Such interferent gases include, for example, nitrous oxide (N.sub.2 O), halothane, enflurane, and isoflurane, which are commonly used in anesthesia gases.
It is very desirable, therefore, to develop a nitric oxide electrochemical gas sensor suitable for use in the medical arts.